The overriding objectives of this proposal are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. The principal classes of structures which will be the focal point for both new reaction methodology and the subject of synthesis activities are largely derived from amino acids. Targets for total synthesis will include the Beta-lactam antibiotics thienamycin, northienamycin, PS-5 and related carbapenems. Two fundamentally different general approaches to the asymmetric synthesis of the Beta-lactam nucleus will be investigated. Other targets for total synthesis will include the powerful antineoplastic agents, saframycin, macbecin, herbimycin, bouvardin, deoxybouvardin, and patellamides A-C. Related targets for total synthesis will include the complex peptide antibiotics of the vancomycin class. Specific objectives within this family include vancomycin, teicoplanin, and restocetin. The major thrust in new reaction methodology which will accompany these target-oriented projects will be the development of new approaches to the asymmetric synthesis of Alpha-amino acids. Within the context of this objective, a number of complementary concepts are outlined. For example, amino acid syntheses based upon the development of chiral glycine enolate synthons, chiral electrophilic aminating agents, and chiral metal nitrenoids are presented.